Result: However, recently, it has been observed that CPSF6 only redistributes to nuclear speckles during WT HIV-1 infection and not during infection with CPSF6-binding deficient mutants A77V and N74D.
Discussion: Furthermore, unlike WT HIV-1, neither the N74D nor the A77V mutant can re-localise CPSF6 to nuclear speckles, showing that this is a CA dependent event.
Discussion: Interestingly, studies with the CPSF6 binding-defective HIV-1 CA mutants, N74D and A77V, have reported that a longer residence time at the nuclear envelope promotes integration into heterochromatin regions close to the nuclear envelope.
MxB sensitivity of HIV-1 is determined by a highly variable and dynamic capsid surface.
Result: As reported, HIV-1 GFP R9 bearing CA mutant N74D, which does not bind the cellular cofactor CPSF6, was insensitive to MxB (Figure 2A,B) and MxB induction did not strongly suppress infection (Figure 2A), viral DNA synthesis, or 2LTR circle formation (Figure 2B).
Result: For example, MxB-insensitive CA mutant N74D is insensitive to depletion of HIV-1 nuclear entry cofactors Nup358, TNPO3, CPSF6 and to some degree Nup153.
Result: This is informative because, like CA mutation N74D, CPSF6 depletion reduces HIV-1 R9 sensitivity to depletion of nuclear entry associated cofactors without impacting infectivity.
Result: To our knowledge this is the first occasion in which the effects of CPSF6 depletion and CA
TRIM34 restricts HIV-1 and SIV capsids in a TRIM5alpha-dependent manner.
Abstract: Through an unbiased screening approach, called HIV-CRISPR, we show that the CPSF6-binding deficient, N74D HIV-1 capsid mutant is sensitive to restriction mediated by human TRIM34, a close paralog of the well-characterized HIV restriction factor TRIM5alpha.
Abstract: Through immunofluorescence studies, we show that TRIM34 and TRIM5alpha colocalize to cytoplasmic bodies and are more frequently observed to be associated with infecting N74D capsids than with WT HIV-1 capsids.
Introduction: Further, both the HIV-1 P90A capsid mutant and the HIV-1 N74D capsid mutant, referred to hereafter as P90A and N74D respectively, have been shown to be hyp
Frequency of capsid substitutions associated with GS-6207 in vitro resistance in HIV-1 from antiretroviral-naive and -experienced patients.
PMID: 32154864
2020
The Journal of antimicrobial chemotherapy
Abstract: METHODS: Plasma samples from ART-naive or -experienced PLWH, including PI-experienced people, were sequenced and analysed for the presence of capsid variants identified during in vitro resistance selection: L56I, M66I, Q67H, K70N, N74D, N74S and T107N.
Characterization of HIV-1 uncoating in human microglial cell lines.
Abstract: Viruses with capsid mutations N74D and E45A decreased the rate of uncoating in CHME3 cells, but did not alter reverse transcription.
Introduction: We also observed differential uncoating kinetics for the mutant N74D in a HeLa cell line engineered to express TRIM-CypA.
Introduction: We found that the E45A and N74D mutations uncoated slower than wildtype virus, while the mutation A92E uncoated faster than wildtype in OMK cells.
Result: Compared to HIV-GFP, the N74D mutation delayed the process of uncoating and increased the half-life of uncoating to 141 min compared to 62 min for wildtype.
Result: However, if there was a differential effect of cy
The 4th and 112th Residues of Viral Capsid Cooperatively Modulate Capsid-CPSF6 Interactions of HIV-1.
PMID: 31941344
2020
AIDS research and human retroviruses
Introduction: The binding process includes an interaction with CPSF6 through the CA N-terminal domain (NTD) as well as through the CA C-terminal domain (CTD); specifically, mutations in the respective CA domains, such as N57A or N74D (NTD) or K182R (CTD), have been shown to reduce CPSF6 binding by HIV-1 CA.
Result: On the other hand, the N74D virus, a CPSF6 binding-deficient CA mutant, was not affected by CPSF6-358.
Multiple Pathways To Avoid Beta Interferon Sensitivity of HIV-1 by Mutations in Capsid.
Introduction: Specifically, it was reported that the CypA binding-deficient CA mutant (the P90A mutant) and the CPSF6 binding-deficient CA mutant (the N74D and A105T mutant) are more sensitive than wild-type (WT) CA to IFN alpha (IFN-alpha) in monocyte-derived THP-1 cells.
Discussion: A similar phenotype was observed with N74D and P90A CA mutants in terms of type I IFN hypersensitivity and resistance to MxB.
Discussion: CPSF6 is a host factor that is capable of modulating the
Discussion: also proposed that inappropriate uncoating kinetics might account for the higher type I IFN sensitivity of the N74D virus.
Nup153 Unlocks the Nuclear Pore Complex for HIV-1 Nuclear Translocation in Nondividing Cells.
Abstract: Analysis of integration sites in HIV-1 viruses with N57 mutations revealed diminished integration into transcriptionally active genes in a manner resembling that of HIV-1 in CPSF6 knockout cells or that of HIV-1-N74D.
Single HIV-1 Imaging Reveals Progression of Infection through CA-Dependent Steps of Docking at the Nuclear Pore, Uncoating, and Nuclear Transport.
Discussion: Importantly, consistent with the nuclear penetration distances of the viral DNA for WT and N74D CA, the N74D mutant complexes failed to undergo significant transport into the nucleoplasm after uncoating at the NE.
Discussion: Our live cell imaging experiments revealed the requirement for nuclear pore-associated uncoating of N74D complexes.
Discussion: The delayed completion of uncoating of docked N74D mutant cores at the NE compared to WT cores.
Discussion: The use of an alternative nuclear import pathway by the N74D CA mutant has been shown to alter the HIV-1 integration sites.
Discussion: This result suggests that the difference in the integration site preference for the PMID: 28727807
2017
PLoS pathogens
Abstract: Analysis of >400,000 unique integration sites showed that WT virus integrated more frequently than N74D mutant within or near genes susceptible to repression by digoxin and involved in T-cell activation and cell metabolism.
Abstract: Using a selective high-throughput chemical screen, we discovered that the cardiac glycoside digoxin inhibits wild-type HIV-1 infection more potently than HIV-1 bearing a single point mutation (N74D) in the capsid protein.
I
Introduction: Certain CA point mutations, such as N74D, are independent of Nup358, Nup153, CPSF6 and TNPO3 for infection, and show a different integration site selection compared to wild type virus.
Introduction: Compound libraries are screened to find selective hits that inhibit WT more than N74D.
HIV mutation literature information.
PMID: 
2021
PLoS pathogens
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